The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
A neoplasm is an abnormal mass or colony of cells produced by a relatively autonomous new growth of tissue. Most neoplasms arise from the clonal expansion of a single cell that has undergone neoplastic transformation. The transformation of a normal cell to a neoplastic cell can be caused by a chemical, physical, or biological agent (or event) that alters the cell genome. Neoplastic cells are characterized by the loss of some specialized functions and the acquisition of new biological properties, foremost, the property of relatively autonomous growth. They pass on their heritable biological characteristics to progeny cells. Neoplasms may originate in almost any tissue containing cells capable of mitotic division.
The past, present, and future predicted biological behaviour, or clinical course, of a neoplasm is further classified as benign or malignant, a distinction of great importance in diagnosis, treatment, and prognosis. A malignant neoplasm manifests a greater degree of autonomy, is capable of invasion and metastatic spread, may be resistant to treatment, and may cause death. A benign neoplasm, however, exhibits a lesser degree of autonomy, is usually not invasive and does not metastasize. Cancer is second only to heart disease as the most common cause of death in western countries. The estimated incidence of cancer in the US, for example, is about 1×106 new cases annually. Nearly 80% of all malignant neoplasms arise in 10 anatomical sites, namely lung, breast, colon and rectum, prostate, lymph nodes, uterus, bladder, pancreas, blood and stomach.
Metastatic tumours are very common in the late stages of cancer. The spread of metastases may occur via the blood, the lymphatics or through both routes, with the most common places for metastases to arise being the lymph nodes, lungs, liver, brain and the bones.
There is a propensity for certain tumours to seed in particular organs. This was first discussed as the “seed and soil” theory by Stephen Paget over a century ago in 1889. For example, prostate cancer usually metastasises to the bones. In a similar manner, colon cancer has a tendency to metastasise to the liver while, in women, stomach cancer often metastasises to the ovary. According to the “seed and soil” theory, it is difficult for cancer cells to survive outside their region of origin, so in order to metastasise they must find a location with similar characteristics. For example, breast tumour cells, which gather calcium ions from breast milk, metastasise to bone tissue, where they can gather calcium ions from bone. Malignant melanoma spreads to the brain, presumably because neural tissue and melanocytes arise from the same cell line in the embryo.
Metastasis involves a complex series of steps in which cancer cells leave the original tumour site and migrate to other parts of the body via the bloodstream or the lymphatic system. To do so, malignant cells break away from the primary tumour and attach to and degrade proteins that make up the surrounding extracellular matrix, which separates the tumour from adjoining tissue. By degrading these proteins, cancer cells are able to breach the extracellular matrix and escape.
The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressors, of which about a dozen are known. It has also been determined that one of the critical events required is the growth of a new network of blood vessels, that is tumour angiogenesis. Significant research has therefore focussed on angiogenesis inhibitors as a means to prevent the growth of metastases. Despite these findings, however, the effective treatment of metastatic cancer has been elusive and largely still relies on the application of very non-specific and highly toxic chemotherapy based methods.
Equally elusive has been the development of a method for the early diagnosis of metastatic cancer. Where metastatic cancer is found at the same time as the primary tumour, often in the context of surgery, the prognosis for the patient is usually very poor due to the advanced stage of disease. However, in patients with either an advanced stage but non-metastasised primary tumour or those in whom metastasis has only just commenced, confirmation of metastatic cancer can be virtually impossible to make due to the limitations of current diagnostic techniques. In these patients the primary tumour will be removed and the patient may nevertheless be subjected to a full course of chemotherapy in the hope that this will be effective to kill any metastatic tumours which may be present. However, in the absence of having positively identified any such tumours it is difficult to assess the necessity of this treatment regime. A still further complicating factor is that not all primary tumours will necessarily metastasise and it is virtually impossible, based just on histological analysis, to predict which tumours will metastasise and which will not. In other situations, there will be no chemotherapy provided for possible metastases and if these in fact exist, they will ultimately not be identified until it is virtually too late for effective treatment.
To this end, there is a significant need to develop means of accurately determining the likelihood of a primary tumour becoming metastatic. The current histology based analysis of primary tumours is highly subjective and not all that accurate. The development of a means to reliably and routinely assess a patient presenting with a primary tumour, to determine the likelihood of the onset of metastatic cancer, is therefore highly desirable.
In work leading up to the present invention, a molecular signature has been identified which, if present in a primary tumour, is characteristic of the propensity of that tumour to metastasise. Specifically, downregulation in a tumour of the level of expression of genes which comprise an IRF7 binding site, relative to the levels present in a non-metastatic tumour, is indicative of the presence of a metastatic phenotype. This finding has therefore now provided a sensitive and reliable means to identify tumours which have, or are likely to, metastasise. This information in relation to the classification of the tumour can then inform the development of the therapeutic treatment and ongoing monitoring which is appropriate for the patient.
Still further, this finding has also facilitated the development of a method for therapeutically or prophylactically treating metastatic cancer based on upregulating the levels of Type I interferon in patients diagnosed with primary tumours exhibiting reduced expression levels of the subject gene signature.